Poisons and Poisoning

Slide 1

Nick Holford Dept Pharmacology & Clinical Pharmacology University of Auckland, New Zealand

Slide 2 Poisons and Poisoning

farmakon pharmakon

Medicine Poison Magic Spell

➢ Learn some typical signs of acute drug poisoning

➢ Understand the pharmacological basis for enhancing elimination of drugs

➢ Understand the pharmacological basis for the use of specific antidotes

➢ History

» Patients rarely lie

» But may be unreliable – Sedation – Amnesic drug effects

©NHG Holford, 2021 all rights reserved. Slide MDMA 3,4- 5 Methylenedioxymethamphetamin e Diagnosis http://en.wikipedia.org/wiki/MDMA BZP benzylpiperazine http://en.wikipedia.org/wiki/Benzyl ➢ Pupils piperazine » Constricted

– opiates (morphine) – clonidine – anti-cholinesterases (neostigmine) » Dilated – atropine – tricyclic antidepressants (amitriptyline) – amphetamine/MDMA (‘ecstasy’)/BZP (‘party pills’)

➢ Skin » Sweating – Increased amphetamine – Decreased atropine

» Bullae – carbon monoxide – [barbiturates]

➢ Odour » ethanol » garlic – arsenic – organophosphates (anti-cholinesterase) » almonds – cyanide

➢ Clinical Chemistry » Blood – salicylate – paracetamol – ethanol – carbon monoxide – tricyclics – digoxin – theophylline

➢ Clinical Chemistry » Urine – salicylate – opioids – tricyclics

➢ ECG » Long PR – Calcium Channel – Verapamil » Wide QRS – Sodium Channel – Amitriptyline » Long QT – Potassium Channel – Amiodarone

➢ General Supportive » A Airway » B Breathing » C Circulation

©NHG Holford, 2021 all rights reserved. Slide Treatment of corrosive ingestion 12 is reviewed here: Hoffman RS, Burns MM, Gosselin Decrease Absorption S. Ingestion of Caustic Substances. N Engl J Med. 2020;382(18):1739-48. ➢ [emesis] http://en.wikipedia.org/wiki/Activat » syrup of ipecac ed_charcoal ➢ [gastric lavage] http://en.wikipedia.org/wiki/Fuller's _earth » must have reflexes

» not for corrosives/hydrocarbons Note that treatment of paraquat poisoning seems to be rarely ➢ activated charcoal - IMPORTANT effective. » 50g every 4 h Gawarammana IB, Buckley NA. ➢ Fuller’s Earth (or activated charcoal) Medical management of paraquat ingestion. Br J Clin Pharmacol. » paraquat (herbicide) 2011;72(5):745-57.

Slide Note also fomepizole may be 13 used to treat ethylene glycol and methanol poisoning Increase Elimination (https://en.wikipedia.org/wiki/Fom epizole)

➢ Activated Charcoal » “enteral dialysis” ➢ Haemoperfusion » charcoal theophylline » ion exchange salicylate ➢ Haemodialysis » methanol (wood alcohol) » ethylene glycol (anti-freeze) ➢ [Diuresis] ©NHG Holford, 2021 all rights reserved. Slide https://en.wikipedia.org/wiki/Fome 14 pizole

Specific Antidotes Naloxone is licensed in NZ as a nasal spray https://nzf.org.nz/nzf_7017 . This ➢ N-acetylcysteine formulation is intended for » paracetamol emergency use by non-health professionals but is currently only ➢ Naloxone available on prescription. » morphine Naloxone is available in the USA for over the counter sale from ➢ Flumazenil pharmacies (Cohen et al 2020). » benzodiazepines Cohen BR, Mahoney KM, Baro E, ➢ Ethanol Squire C, Beck M, Travis S, et al. » methanol FDA Initiative for Drug Facts Label for Over-the-Counter ➢ Fomepizole Naloxone. N Engl J Med. » ethylene glycol, methanol 2020;382(22):2129-36.

©NHG Holford, 2021 all rights reserved. Slide Pollack CV, Reilly PA, Eikelboom 15 J, Glund S, Verhamme P, Specific Antidotes Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. N Engl J ➢ Chelation Med. 2015 DOI: » desferrioxamine iron 10.1056/NEJMoa1502000 » edetate lead » penicillamine copper, mercury Eddleston M, Chowdhury FR. » hydroxocobalamin cyanide Pharmacological treatment of organophosphorus insecticide ➢ Atropine/pralidoxime poisoning: the old and the » anti-cholinesterases (possible) new. Br J Clin Pharmacol. 2015:doi:10.1111/bcp.12784. ➢ Phytomenadione (vitamin K1) » Warfarin andexanet (not in NZF) Andexxa—an antidote for ➢ Protein Binding Agent apixaban and rivaroxaban. JAMA. » digoxin F(ab) digoxin 2018;320(4):399-400. » idarucizumab F(ab) dabigatran The reversal agent, PB2452 (not » andexanet apixaban, rivaroxaban in NZF) is a monoclonal antibody ©NHG Holford, 2021 all rights reserved. fragment that binds ticagrelor (an anti-platelet agent) with high affinity; Bhatt DL, Pollack CV, Weitz JI, Jennings LK, Xu S, Arnold SE, et al. Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers. N Engl J Med. 2019;380(19):1825-33.

Slide Siegal DM, Curnutte JT, Connolly 16 SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet Alfa for the Anti Factor Xa Activity Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;doi:10.1056/NEJMoa151099 1.

©NHG Holford, 2021 all rights reserved. Slide “Paracetamol poisoning is the 17 most common acute overdose seen in industrialized countries [1, Specific Antidote 2]. It is estimated that between 82 000 and 90 000 patients present ➢ Paracetamol Hepatotoxicity in the UK each year with paracetamol overdose [3–5]. » Minor metabolite is NAPQI (N- acetyl-p-benzoquinoneimine) Between 150 and 250 deaths – Formed by CYP2E1 occur annually, the vast majority – Ethanol induces CYP2E1 in patients who have presented » NAPQI inactivated by glutathione late, after a staggered overdose » Liver damage caused by NAPQI or after unintentional therapeutic » Glutathione reserves used up by large doses (> 15 excess [6–9]. Deaths or episodes grams of paracetamol) of liver failure in patients [10] who present and are treated within 8 h of a single acute ingestion are ➢ Acetylcysteine supplies SH to make more glutathione extremely rare [1, 5, 11].” ➢ UK guidelines (2014) for treatment shown to be cost- Bateman DN, Carroll R, Pettie J, ineffective Yamamoto T, Elamin MEMO, Peart L, et al. Effect of the UK's revised paracetamol poisoning ©NHG Holford, 2021 all rights reserved. management guidelines on admissions, adverse reactions and costs of treatment. Br J Clin Pharmacol. 2014;78(3):610-8.

Ethanol can induce and “block” CYP2E1 at the same time. The "blocking" of metabolism of ethanol by itself is a manifestation of mixed-order saturable elimination as shown by the associated decrease in 'clearance' due to concentration dependent clearance.There are four processes involved in the paracetamol and ethanol interaction which are based on the same underlying mechanism of binding to CYP2E1. 1. Metabolism of ethanol by CYP2E1 2. Induction of CYP2E1 by ethanol 3. Metabolism of paracetamol by CYP2E1 4. Inhibition of paracetamol CYP2E1 metabolism by ethanol When ethanol binds to CYP2E1 it is metabolized and with continued ethanol binding the CYP2E1 protein is induced so that the enzyme becomes more active and metabolism is faster. When paracetamol binds to CYP2E1 it is metabolized to NAPQI. If ethanol is present and bound to CYP2E1 then paracetamol metabolism to NAPQI is reduced because of competition for the same binding site. The process of induction and de- induction is gradual with a protein turnover half-life of about 3 days so it takes about 2 weeks to induce and 2 weeks to de-induce. When ethanol binding is no longer present then the CYP2E1 protein decreases (de-induction) and enzyme activity returns to the uninduced state. If CYP2E1 has been induced and ethanol is stopped (and therefore not bound to CYP2E1) then paracetamol will be metabolized more quickly to NAPQI. As CYP2E1 becomes de-induced the metabolism of paracetamol will decrease until activity returns to the uninduced state. The risk of hepatotoxicity from paracetamol metabolism to NAPQI will be higher when CYP2E1 is induced and there is no ethanol present than the risk if ethanol is present. Thummel KE, Slattery JT, Ro H, Chien JY, Nelson SD, Lown KE, et al. Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults. Clin Pharmacol Ther. 2000;67(6):591-9.

A “two bag” 12 h administration of acetylcysteine appears to be safer. Chiew AL, Isbister GK, Duffull SB, Buckley NA. Evidence for the changing regimens of acetylcysteine. Br J Clin Pharmacol. 2016;81(3):471-81.

Slide http://www.merck.com/mmpe/sec 18 N-Acetylcysteine Treatment Nomogram 21/ch326/ch326c.html

for Paracetamol Overdose in Adults Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatrics. 1999;135(3):290-5.

Children: 225 mg/L at 2 hours Anderson et al. 1999 [Auckland]

➢ Approach to Poisonings » ABC and General Support » Specific antidotes are uncommon

➢ Use physiology and pharmacology to assist in diagnosis

➢ Consider factors affecting drug clearance if enhanced elimination procedures are used

©NHG Holford, 2021 all rights reserved. Slide Henretig FM, Kirk MA, McKay CA. 20 Assessment Short Answer Hazardous Chemical Emergencies and Poisonings. N Question Examples Engl J Med. 2019;380(17):1638- 55.

1. Give an example of a physical sign of drug poisoning and a medicine causing this.

2. Explain how activated charcoal may enhance the elimination of drugs.

3. What specific antidote may be used to treat cyanide poisoning?